The goal of this research is to understand the neural mechanisms by which inflammatory cytokines cause anorexia, weight loss, and lethargy. This constellation of findings closely resembles cachexia, a state of disease-associated wasting common to many chronic diseases. Cachexia dramatically reduces quality of life and increases mortality and morbidity. Further, there are currently no effective treatments available. Previous work has established that central administration of inflammatory cytokines can recreate all of the cardinal features of cachexia. Though the mechanism by which one inflammatory cytokine, IL-1b, causes the metabolic changes has been described, it is currently unknown whether other anorectic cytokines work in the same way. Specific aim I of the proposed research will evaluate whether leukemia inhibitory factor (LIF), an inflammatory cytokine elevated in chronic disease, reduces food intake and increases metabolic rate by directly activating proopiomelanocortin (POMC) neurons in the arcuate nucleus ofthe hypothalamus. This will be tested by verifying an anatomic basis for LIF activation exists on POMC neurons using histochemical approaches. The response of these neurons in the presence of LIF will be monitored in vivo and ex vivo and will be correlated to whole animal physiology in wild-type and transgenic mice which are deficient in LIF signaling in arcuate POMC neurons. The means by which inflammation causes lethargy also have not been described. Recent research has implicated the role of orexin neurons in the maintenance of arousal and somnolence. Specific aim II will test the hypothesis that a decrease in orexin neuron activity mediates inflammation-induced lethargy. Using a tumor bearing model of chronic inflammation, activity of orexin neurons will be evauated histochemically and correlated to measurements of motor activity, food intake, and body composition. A central cytokine administration model of cachexia will also be utilized, and the effectiveness of orexin replacement in restoring activity and feeding behavior will be evaluated. Cachexia, a wasting syndrome common to the late stages of many chronic diseases, severely limits a patient's ability to fight their condition or receive treatment. Though cachexia is estimated to affect as much as 2% of the population, there is currently no effective treatment. This research is designed to understand how disease causes these devastating reductions in eating and activity level as a means to develop new therapies.